Background: Recent natural history studies suggest that MS is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach.

Objectives: The researchers investigated whether MS disease progression has changed over time in British Columbia, Canada.

Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration.

Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant trend was found in the proportion of patients reaching EDSS 6 (needing a walking stick) within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09).

Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

"This is disappointing as we would hope the introduction of DMTs would have an impact on the rate of disease progression."

"We must not forget that the first-line therapies are not that effective and that too few subjects may have been followed in this cohort too see the impact of DMTs on disease progression rates; i.e. this study was under powered."

"We will need to wait to see the impact of the next generation of treatments on disease progression. If there is no effect we have got the facts or current dogma about MS wrong."

Objective: To determine the frequency and risk factors of post-LP headache (PLPH) in research volunteers.

Background: Despite increasing interest in measuring cerebrospinal fluid (CSF) biomarkers to investigate disease pathogenesis and diagnosis, previous case series have evaluated lumbar puncture (LP) safety only in clinical care. PLPH is a common complication after LP.

Methods: We determined the frequency of PLPH in adults volunteering for research, as well as the variables associated with the development of PLPH. Variables studied were body mass index (BMI), HIV serostatus, volume of CSF removed, number of previous LPs, use of pre-medication, LP position, lumbar space, number of needle passes, whether or not aspiration was used and several CSF variables.

Conclusion: In this study, where tolerance to risk was low because LPs were done for research rather than clinical purposes and healthy controls were included, adverse effects were mild and self-limited.

"This study is reassuring in that the incidence of post-LP headache is lower than the figure we normally quote subjects, i.e. 10%. In addition, the majority resolved spontaneously."

"An epidural blood patch is when we inject fresh blood taken from your arm into the space around the lower spine. The blood then clots and seals off the hole through witch the spinal fluid leaks. This is a very simple procedure."

The response to our call for progressive and other MS'ers to watch this video and complete the survey has been surprisingly poor (14 respondents so far). It makes me wonder about all the complaining progressive MS'ers do in relation to there being no treatments for progressive disease and the lack of research. Without a clear signal from you that you are prepared to have lumbar punctures as part of a clinical trial the less likely we are to be able to test this study design, which I think is very innovative.

In addition, it is an output of the Promise 2010 programme. Many of you complained that this programme did not deliver on its promise. I disagree! The Promise 2010 programme was a partnership between MS researchers and MS'ers; we need you to help translate the insights from the programme.

If you are willing to help can you please watch the video above before completing the survey; questions in the survey relate to issues presented in the video: MS LP Survey.

Tuesday, 27 September 2011

You have again been searching the News again and there has been some debate amongst the bloggers, about a report from Cleveland Ohio, USA by Najm et al. Nature Methods 24 Sept.

It is good that you Bloggers posts things and maybe we can have a new feature(Mouse)Doctoring the News!

This is what this Blog is about unravelling the Research News..Bad or Good..

As you must realise we at Team G believe that getting myelin back onto nerves is a real priority to help all MSers, whether you have progressive Ms or not. It has been a difficult ask because until we can put the flames of MS out, adding myelin back is like putting wood on a fire. However, we have been making distinct in-roads in the fire extinguisher department, so this new publication is highly topical.

The team from Ohio have taken pluripotent stem cells (means they can grow into any cell type in the body) and then using a cocktail of growth factors and inhibitors and stimulators that are applied at different time points in the development of the cells they have been able to make alot of oligodendrocytes-the cells that make myelin.

Whilst this has been done in the past, the importance of this study is that it can be done consistently and this a is a great step forward for anyone working in the field of myelin repair, as it gives a source of cells that:

(a) Allows us to reduce animal use (as these are normally a source for these cells).(b) Have a large number of cells to be able to understand and study this process.(c) We have large numbers of cells do that we can design assays to hunt for drugs that can promote the production and differentiation of myelin cells for treatments (as it would be too complicated to use the cocktails of chemicals that the researchers used in the study to do this in people with MS). The researchers showed evidence that this a possibility.(d) It provides us with a source of cells that we can use to see it they can overcome the problems created by MS in experimental models. This study showed that the cells grown could make myelin in animals that naturally lack myelin. However, it is one thing to find ways to make myelin-forming cells, it is another thing to ask then to get into a scar and repair the myelin after the damage has been around for some time. However, addressing these questions will inform how best to apply the knowledge to MS

These are are all vital steps in helping to get drugs to help MS.

What this study does not say (the media might), is that now we can make millions of cells for treatment of MSers. This is only a step moving towards this goal.

We first need to see how this study in mice can be applied to making human cells. This is important because we know that not all of the factors that trigger this process in mice are used by human cells to do the same thing.

However it shows proof of principle that it can be done! So why can't it be done for human cells?...No reason at all, it is just a question of hard slog, a bit of inspiration and finding the right combination of growth factors, inhibitors and stimulators. This study by the mousErs will no doubt stimulate the humanErs to help them find the answers for making human myelinating cells.

Paul Knoepfler: 'Any procedure involving removing cells from the body and manipulating them — even if it's something as simple as centrifuging them or putting them in a plastic tube — and then putting them elsewhere in the body poses risks.'

Paul Knoepfler: 'Patient testimonials cited by the people selling the treatments have little if any meaning.'

Kirstin Matthews: 'I do believe governor Perry is pushing research to the clinic too quickly.'

Bettie Sue Masters: 'I feel that we must protect patients from risky treatments advanced by overzealous, even greedy, entrepreneurs.'

"What is unbelievable is that, Texas governor Rick Perry, and Presidential candidate, had treatment with his own stem cells to treat a back complaint. The procedure was carried out by Stanley Jones, a surgeon based in Houston, Texas, who specialises in cosmetic procedures and who is a friend of Rick Perry."

"Politicians, like neurologists, have social responsibilities and need to realise that their actions may have unexpected consequences. I would be interested to meet Rick Perry's scientific adviser or advisers."

"We really need an open debate about stem cell therapies so that we can try and prevent MS'ers from taking unnecessary risks and being exploited by Charlatans."

"At present, no MS'ers should be receiving stem cell therapy outside of a clinical trial and they should definitely not be having to pay for it. At the moment stem cell therapy is experimental."

MRI of cortical lesions (gray matter on the surface of the brain*)due to MS has been hampered by the lesions' small size and low contrast to adjacent, normal-appearing tissue.

* the cortex of the brain is where specialised cognitive tasks occurs; MS lesions in the cortex are responsible for cognitive dysfunction (memory impairment, etc.) that occurs in the majority of MS'ers.

In this study 8 MS'ers and 7 healthy control subjects were scanned at 7 Tesla (most conventional MRI scanners are 1.5 or 3 Tesla; Tesla refers to power of the magnet).

White matter and gray matter lesions were significantly higher in MS'ers than in controls. Large numbers of cortical and white matter lesions were noted in MS for the first time.

Ultrahigh field MR imaging will be important for future investigations in MS research, particularly the detection of cortical lesions.

"The introduction of ultra high-field MRI will allow us to monitor the effects of MS in the cortex of the brain. Todate the lesions in this area have been invisible on MRI. We know from pathological studies that about 50% of the disease burden occurs in the gray matter. This study and other like it enlarges the iceberg that is MS; now we will be able to see more of the iceberg that is subclinical."

Friday, 23 September 2011

"Daily pill to prevent or even cure multiple sclerosis in pipeline"

They say “This is frankly an exciting breakthrough and has huge potential. The role of neurosteroids in the brain has been known for some time but no one thought, until now, that they might play a role in MS...When mice with MS were treated with the neurosteroid it cut inflammation in the brain and repaired nerve fibres and their protective myelin sheaths...We found the mice showed a 50% reduction in MS disease severity in the brain."

MouseDoctor says 50% reduction IS NOT A CURE, this is bad reporting and over-hyping again creating false expectations... so lets look at the story.

Whilst looking for molecules that can influence how proteins are made, researchers found that some of these molecules seemed to converge on a pathway that makes allopregnanlone. Allopregnanlone modulates certain chemicals in the brain that control how nerve impulses fire. Therefore, there are many potentials for a drug that mimics this and also potential side-effects (such as cognitive behaviours). The researchers found that there was less Allopregnanlone in the brains of MSers and also in the animal MS models. The researchers then gave allopregnanlone to mice with MS-like disease.

Viewing the data it looks like there is some immunomodulating effect of the drug and so the claims of benefit on sparing of myelin and nerve injury are obvious, because if the damaging immune response does not arrive to cause damage, it is obvious that there will not be any damage. (Remember we want more than just this effect) Therefore, they did not show evidence that this drug actually causes nerve repair in the animals. In my opinion the experiment was not designed so that it could show this. Also it looks like the drug did not completely prevent disease from occuring, so again this has not yet been shown to be a cure. So the claims in paper were over-hyped and need more experiments are needed to show this.

However, on the real positive side, the researchers provided evidence that this drug could influence the growth and maturation of cells that make myelin. This linked with evidence from other animals studies that allopregnanlone may slow the accumulation of nerve damage, suggests that there may be real mileage in investigating this pathway, for progressive MSers, so this aspect makes it more exciting and it is promise for the future.

However, in the animal studies this drug is not even in pill form and so it will be many years, before there is a drug-based on this would reach MSers.

Background: Spasticity (stiffness of muscles) presumably affects mobility and balance. This study examined whether or not MS'ers with spasticity in their lower legs have more impairment of mobility and balance compared to those without spasticity.

Results: 15 MS'ers had spasticity of the calf muscles based on the modified Ashworth scale scores. The spasticity group had greater disability (P=0.03). Mobility and balance were significantly more impaired in the group with spasticity compared to the group without spasticity.

Discussion: Spasticity in the calf muscles has a negative effect on mobility and balance in MS'ers. The relationship between spasticity and disability in persons with MS requires further exploration.

"As a neurologist this study is stating the obvious, i.e. MS'ers with spasticity are more disabled. In MS spasticity and weakness go hand-in-hand so the findings of this study are not surprising. What is more important is early spasticity; when MS'er start to realise that they have stiffness and muscle spasms as a result of their disease. Does treating spasticity at this stage improve physical functioning?"

"Unfortunately, the licensed drugs for spasticity are associated with unpleasant side effects, mainly sedation and poor cognition; we therefore tend to delay initiaiting them for as along as possible."

"Our group are working on developing new anti-spasticity drugs with fewer side effects to overcome this problem."

"An important exception to starting anti-spasticity drugs is night-time leg spasms that often wake MS'ers in the early hours of the morning or interrupt their sleep. This often leaves MS'ers tired in the morning due to poor quality sleep. In my experience this is also an important contributor to MS-related fatigue. Giving a longer acting anti-spasticity drug at night, for example clonazepam, often helps resolve this problem and improves MS'ers daytime functioning."

"It is also important to make sure that any bladder problems are addressed at the same time as night time leg spasms; having to get up frequently at nigh to pass urine is another cause of poor sleep. We also have medication to treat this problem."

"So if you have night-time leg spasms or bladder problems that are affecting your sleep please discuss this with your neurologist so that you can be treated. You will be surprised how much better you feel after a good nights sleep."

Purpose of review: The function and use of vitamin D supplementation has become very controversial. This review attempts to provide a balanced perspective with respect to the experimental findings published in the past 18 months.

Recent findings: The recent contrasts between the Institute of Medicine (IOM) report and the Endocrine Societies report have caused great confusion with respect to the dietary requirement for vitamin D as well as the amount of circulating 25-hydroxyvitamin D that is desirable. Much recent data contradict the suggestions of the IOM report with respect to vitamin D's role in chronic disease such as cancer, cardiovascular function, immune function and autoimmune ailments such as multiple sclerosis.

Summary: Controversy regarding supplementation with vitamin D is fueled by the different purposes of the IOM (guidance for food fortification and not to individualized patient care) and the Endocrine Societies (patient care) reports. Healthcare providers should formulate their own opinions with respect to vitamin D as it pertains to the care of their patient.

"Bruce Hollis the vitamin D sage has obviously written this review to address the discordant advice regarding levels of vitamin D supplementation for food fortification (public health) and clinicians (patient care). The bottom line is you need to be vitamin D replete and in the UK this requires a daily requirement of ~10,000U per day over the year (5,000 from diet and sunshine and 5,000 from supplements)."

"If you are new to this blog please check-out some of the previous posts on this blog that relate to vitamin D in MS. It is clear that this is a big issue for MS'ers."

"We know from numerous other studies that being deficient in vitamin D affects your immunity and increases your risk of infections and probably relapses." "This study is another reason to make sure that you are vitamin D ...

We need sufficient amount of sunlight exposure to synthesis our body's requirement of vitamin D; this does not happen in Britain and many parts of the world. Change in behaviours is contributing to vitamin D deficiency: ...

This allowed these investigators to study the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum vitamin D during pregnancy and their daughters' risk of developing MS. ...

17 Jul 2011

In Australia and New Zealand, the number of people with vitamin D deficiency varies, but is acknowledged to be much higher than previously thought. One study found marginal deficiency in 23% of women, and another frank ...

The Endocrine Society's guidelines, call people with levels under 50 nmol/L "vitamin-D deficient", and those with levels between 50 nmol/L and 72.5 nmol/L "insufficient". The society's guidelines also offer an 'ideal' level of ...

"This study provides a hint that vitamin D supplementation that results in higher blood vitamin D levels many suppress EBV within the body. Interesting? We think very interesting and trying to work out how EBV and vitamin D ...

This study compared vitamin D status in 200, free-living, woman, aged between 20 to 55 years, from Tehran, a high-polluted area, and Ghazvin, a low-polluted area. Level of UVB (ultra-violet B - the part of the light spectrum ...

The active metabolite of vitamin D is a potent modulator of immune cells. In this study the investigators' determined whether vitamin D, a sun-dependent nutrient can affect the cells athat are associated with the immune ...

Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions on MRI. ...

This study compared the relative potencies of vitamins D2 and D3 by giving a single dose of 50000 IU of the respective vitamins to 20 healthy male volunteers and followed the time course of blood vitamin D aover a period of ...

Sunlight, Vitamin D and EBV. More about the environmental risk factors that increase susceptibility to MS. "What we now need is a study to integrate these risk factors. Would you be interested in participating?" Posted by Gavin ...

Vitamin D Supplement Doses and Serum 25-Hydroxyvitamin D in the Range Associated with Cancer Prevention. How safe are high dose Vitamin D3 (vD3) supplements? In this study on over 3600 study participants ~25% of ...

Can vitamin D(3) supplementation prevent bone loss in persons with MS? A placebo-controlled trial. Osteoporosis (thinning of the bones) is common in MS. In this small study the investigators failed to show that a weekly dose ...

Vitamin D Deficiency and Latitude and Month of Birth. These are probably linked to sunshine which makes Vitamin D in humans. You get less ... This lack of vitamin D may shape how your immune system develops. This may ...

THE AUTHORS' CONCLUSIONS ARE SELF-EXPLANATORY: "The current level of evidence for the effectiveness of vitamin D supplementation in the management of people with MS is based on a single randomised control trial with ...

After our MS Research Day on the 30th January we have been asked by several people about the correct dose of vitamin D to take to try and prevent MS and related disorders. Unfortunately we don't know. ...

The committee of scientists, convened by the National Academies' Institute of Medicine, doubled the upper level of vitamin D that people that people between the ages of 9 and 50 can safely take in any given day from 2000 ...

Vitamin D is crucial for maintenance of the immune system and vD deficiency has been implicated in the causal pathway of MS. In this study genetic variants at three places in the genome were associated with vD levels. ...

Is it a co-incidence that Dr Ruth (Not Westheimer) is next to Dr VD (that's Vitamin D not VD). P.S. If you are a Nutter, Anti-Vivisectionist (non-nutter AV's are OK......we can have a conversation), then Don't Do Your ...

We also make less vitamin D as our body stores D3 and has met it's daily requirement. You cannot overdose on Vitamin D3 from sun exposure as unabsorbed D3 is processed on into supra sterols the body doesn't use. ...

The current hypothesis is that if your mother was pregnant during winter ( and you were born in April), a time when she is more likely to be vitamin D deficient, it affected the development of your immune system making you ...

The effect of UVB on generating vitamin D seems the most likely candidate for explaining its relationship with MS. There is a pressing need to investigate the role of vitamin D and EBV and how they might interact to influence MS risk to ...

We have been slowly building up a picture of how primary progressive MS may develop using transport analogies with cars and underground trains to ask "What is the problem in PPMS?", "Why don't Current MS drugs work in PPMS?"

Now I reshow the first instalment and hope that it is not as complicated as some of you thought when if was first posted (Most thought it was unhelpful)

Relapses are triggered by white blood cells (cars) entering the brain and damaging the oligodendrocyte (0) and nerves (N). This coupled with swelling of the nerve, serves to stop the nerve impulses firing properly. This leads to symptoms.

The best treatments of (relapsing) MS aim at preventing white blood cells (WBC) reaching the brain (carpark) and if this happens it will stop the cascade of damaging events (loss of myelin and nerve damage) from occuring. This is the basis for the action of Tysabri, Gilenya, Mixtoxantrone, Alemtuzumab.

Current effective treatments for relapsing MS work by stopping the white blood cells entering the brain. These (Alemtuzumab, Rituzimab, Cladribine, Bone marrow transplantation, beta interferon) do not appear to stop the non-relapsing aspects of progressive MS.

Therefore we need a new approach to treat progressive MS, because the main problem appears to not be with the white blood cells (although I think that these need to be dealt with also) but appears to be a problem with the nerves, that has been triggered by the damage caused by white blood cells.

Nerves transmit nerve impulses (tube trains) see videos in British or American English to Explain) from one nerve to another across a synapse (interchange. see video). Transmission of the nerve impulse uses energy to transmit the impulse, which results from movement of ions largely sodium (Na) (Black passengers) and potassium. (K) (red passengers) Sodium enters the cell by sodium channels (pores that allow sodium to flow through them) in the nerve. Once the impulse passes the nerve resets itself so that it can transmit the next signal. Within the nerve there is a exchanger (imagine a revolving door). The system pumps calcium (Ca) out of the cell in exchange for sodium. This all helps maintains the health of the cell and te balance of sodium within the cell The myelin sheath made by oligodendrocytes allows the nerve impulse to travel faster. This is because the nerve impulse jumps acrossto the gaps (stations. Nodes of Ranvier) between individual myelin sheaths. (There are lots of videos/tutorials on youtube those by khanacademy.org are informative. (If you watch these- a schwannn celll myelinates peripheral nerves and those in the brain are myelinated by oligodendrocytes but otherwise the message applies to the brain)

As the compensation mechanisms (plasticity) become exhausted or are not there in the first place (from PP MSers) damage from progressive MS takes over from damage caused during relapsing MS.In progressive MS, loss of myelin (tube tunnel) is a feature of the disease. Initially this damage may be repaired. But as we get older our repair mechanisms become less effective. Furthermore the disease may kill too many of the repairing-cells and the scarring from the damage may stop repair. This makes the nerves vulnerable to further damage.

Once nerves are demyelinated, to keep the nerve impulses moving the nerve must use alot more energy. Low level inflammation which is present in all MS types such as that produced by microglial cells produces mediators such as nitric oxide that stop cells from making enough energy. This blocks the action of the energy-dependent sodium-potassium pump. This results in excess sodium entering the nerve, via the sodium channels. This excess sodium in the cell can cause the sodium-calcium exchanger to go into reverse and it pushes sodium out of the cell whilst pulling calcium into the cell. This can be bad news as too much calcium in cells triggers them to commit suicide. (Train stops working) Therefore simple electrical activity of the nerves can be a problem for demyelinated nerves. As nerve circuits are damaged and lost the brain compensates by using different circuits to perform the task. As nerves are lost it puts more of a strain on the remaining nerves, leading to further nerve loss and the accumulation of progressive disability.

With this scenario progressive disease can occur in the absence of white blood cells and explains why current MS drugs are not useful for progressive MSers.

Importantly it gives us clues (Such as sodium, calcium channel blockers, sodium calcium exchanger blockers, glutamate blockers, etc etc,) on how to treat MS. One obvious route is to repair the myelin, but others such as blocking the accumulation of toxic concentrations of ions in the nerve are even more feasible, because these types of drugs are already availble to treat other diseases such as epilepsy.

Some of these studies have already started and more are planned in the new future.

Thursday, 22 September 2011

Question: Do you want to know whether blood or plasma from young animals can stimulate faster remyelination in older animals using the parabiosis experiment?

The majority of you who responded were in favour of performing the parabiosis experiment to determine whether something in young blood helped myelin repair. So with this positive result, you may be pleased to know that these experiments have already been done and progress has moved forward. I won't give you the good news so as not to steal the thunder of the people doing the work because it has yet to officially hit the scientific newstands.

Interestingly, there was a few of you that thought it was wrong to do the experiment but really wanted to get the answer. This highlights the ethical dilemmas that can occur, especially if you have a potential vested interest in the outcome.

All studies on people and other animals that Prof G or the MouseDoctor want to do, go through independent ethical approval processes. So you know not everything gets an easy ride, so it is not a rubber stamping exercise.

PML Risk Infographic

Holistic Management of MS ver. 7.0

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General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

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